Targeting UDP-α-D-glucose 6-dehydrogenase inhibits glioblastoma growth and migration

UDP-glucose 6-dehydrogenase (UGDH) produces UDP-α-D-glucuronic acid, the precursors for glycosaminoglycans (GAGs) and proteoglycans of the extracellular matrix. Elevated GAG formation has been implicated in a variety of human diseases, including glioblastoma (GBM). In our previous study, we found that Krüppel-like factor 4 (KLF4) promotes GBM cell migration by binding to methylated DNA, mainly methylated CpGs (mCpG) and transactivating gene expression. We identified UDGH as one of the downstream targets of KLF4-mCpG binding activity. In this study, we show that KLF4 upregulates UGDH expression in a mCpG-dependent manner, and UGDH is required for KLF4-induced cell migration in vitro. UGDH knockdown decreases GAG abundance in GBM cells, as well as cell proliferation and migration in vitro. In intracranial xenografts, reduced UGDH inhibits tumor growth and migration, accompanied by a decrease in the expression of extracellular matrix proteins such as tenascin C, brevican. Our studies demonstrate a novel DNA methylation-dependent UGDH upregulation by KLF4. Developing UGDH antagonists to decrease the synthesis of extracellular matrix components will be a useful strategy for GBM therapy

The first super-Earth Detection from the High Cadence and High Radial Velocity Precision Dharma Planet Survey

The Dharma Planet Survey (DPS) aims to monitor about 150 nearby very bright FGKM dwarfs (within 50 pc) during 2016$-$2020 for low-mass planet detection and characterization using the TOU very high resolution optical spectrograph (R$\approx$100,000, 380-900nm). TOU was initially mounted to the 2-m Automatic Spectroscopic Telescope at Fairborn Observatory in 2013-2015 to conduct a pilot survey, then moved to the dedicated 50-inch automatic telescope on Mt. Lemmon in 2016 to launch the survey. Here we report the first planet detection from DPS, a super-Earth candidate orbiting a bright K dwarf star, HD 26965. It is the second brightest star ($V=4.4$ mag) on the sky with a super-Earth candidate. The planet candidate has a mass of 8.47$\pm0.47M_{\rm Earth}$, period of $42.38\pm0.01$ d, and eccentricity of $0.04^{+0.05}_{-0.03}$. This RV signal was independently detected by Diaz et al. (2018), but they could not confirm if the signal is from a planet or from stellar activity. The orbital period of the planet is close to the rotation period of the star (39$-$44.5 d) measured from stellar activity indicators. Our high precision photometric campaign and line bisector analysis of this star do not find any significant variations at the orbital period. Stellar RV jitters modeled from star spots and convection inhibition are also not strong enough to explain the RV signal detected. After further comparing RV data from the star's active magnetic phase and quiet magnetic phase, we conclude that the RV signal is due to planetary-reflex motion and not stellar activity.Comment: 13 pages, 17 figures, Accepted for publication in MNRA

The role of input noise in transcriptional regulation

Even under constant external conditions, the expression levels of genes fluctuate. Much emphasis has been placed on the components of this noise that are due to randomness in transcription and translation; here we analyze the role of noise associated with the inputs to transcriptional regulation, the random arrival and binding of transcription factors to their target sites along the genome. This noise sets a fundamental physical limit to the reliability of genetic control, and has clear signatures, but we show that these are easily obscured by experimental limitations and even by conventional methods for plotting the variance vs. mean expression level. We argue that simple, global models of noise dominated by transcription and translation are inconsistent with the embedding of gene expression in a network of regulatory interactions. Analysis of recent experiments on transcriptional control in the early Drosophila embryo shows that these results are quantitatively consistent with the predicted signatures of input noise, and we discuss the experiments needed to test the importance of input noise more generally.Comment: 11 pages, 5 figures minor correction

Indirect reciprocity and the evolution of “moral signals”

Signals regarding the behavior of others are an essential element of human moral systems and there are important evolutionary connections between language and large-scale cooperation. In particular, social communication may be required for the reputation tracking needed to stabilize indirect reciprocity. Additionally, scholars have suggested that the benefits of indirect reciprocity may have been important for the evolution of language and that social signals may have coevolved with large-scale cooperation. This paper investigates the possibility of such a coevolution. Using the tools of evolutionary game theory, we present a model that incorporates primitive “moral signaling” into a simple setting of indirect reciprocity. This model reveals some potential difficulties for the evolution of “moral signals.” We find that it is possible for “moral signals” to evolve alongside indirect reciprocity, but without some external pressure aiding the evolution of a signaling system, such a coevolution is unlikely

Comparing Arabidopsis receptor kinase and receptor protein-mediated immune signaling reveals BIK1-dependent differences

Pattern recognition receptors (PRRs) sense microbial patterns and activate innate immunity against attempted microbial invasions. The leucine‐rich repeat receptor kinases (LRR‐RK) FLS2 and EFR, and the LRR receptor protein (LRR‐RP) receptors RLP23 and RLP42, respectively, represent prototypical members of these two prominent and closely related PRR families. We conducted a survey of Arabidopsis thaliana immune signaling mediated by these receptors to address the question of commonalities and differences between LRR‐RK and LRR‐RP signaling. Quantitative differences in timing and amplitude were observed for several early immune responses, with RP‐mediated responses typically being slower and more prolonged than those mediated by RKs. Activation of RLP23, but not FLS2, induced the production of camalexin. Transcriptomic analysis revealed that RLP23‐regulated genes represent only a fraction of those genes differentially expressed upon FLS2 activation. Several positive and negative regulators of FLS2‐signaling play similar roles in RLP23 signaling. Intriguingly, the cytoplasmic receptor kinase BIK1, a positive regulator of RK signaling, acts as a negative regulator of RP‐type immune receptors in a manner dependent on BIK1 kinase activity. Our study unveiled unexpected differences in two closely related receptor systems and reports a new negative role of BIK1 in plant immunity

Double-Stranded RNA Attenuates the Barrier Function of Human Pulmonary Artery Endothelial Cells

Circulating RNA may result from excessive cell damage or acute viral infection and can interact with vascular endothelial cells. Despite the obvious clinical implications associated with the presence of circulating RNA, its pathological effects on endothelial cells and the governing molecular mechanisms are still not fully elucidated. We analyzed the effects of double stranded RNA on primary human pulmonary artery endothelial cells (hPAECs). The effect of natural and synthetic double-stranded RNA (dsRNA) on hPAECs was investigated using trans-endothelial electric resistance, molecule trafficking, calcium (Ca2+) homeostasis, gene expression and proliferation studies. Furthermore, the morphology and mechanical changes of the cells caused by synthetic dsRNA was followed by in-situ atomic force microscopy, by vascular-endothelial cadherin and F-actin staining. Our results indicated that exposure of hPAECs to synthetic dsRNA led to functional deficits. This was reflected by morphological and mechanical changes and an increase in the permeability of the endothelial monolayer. hPAECs treated with synthetic dsRNA accumulated in the G1 phase of the cell cycle. Additionally, the proliferation rate of the cells in the presence of synthetic dsRNA was significantly decreased. Furthermore, we found that natural and synthetic dsRNA modulated Ca2+ signaling in hPAECs by inhibiting the sarco-endoplasmic Ca2+-ATPase (SERCA) which is involved in the regulation of the intracellular Ca2+ homeostasis and thus cell growth. Even upon synthetic dsRNA stimulation silencing of SERCA3 preserved the endothelial monolayer integrity. Our data identify novel mechanisms by which dsRNA can disrupt endothelial barrier function and these may be relevant in inflammatory processes

Very Low Mass Stellar and Substellar Companions to Solar-Like Stars From MARVELS V: A Low Eccentricity Brown Dwarf from the Driest Part of the Desert, MARVELS-6b

We describe the discovery of a likely brown dwarf (BD) companion with a minimum mass of 31.7 +/- 2.0 M_Jup to GSC 03546-01452 from the MARVELS radial velocity survey, which we designate as MARVELS-6b. For reasonable priors, our analysis gives a probability of 72% that MARVELS-6b has a mass below the hydrogen-burning limit of 0.072 M_Sun, and thus it is a high-confidence BD companion. It has a moderately long orbital period of 47.8929 +0.0063/-0.0062 days with a low eccentricty of 0.1442 +0.0078/-0.0073, and a semi-amplitude of 1644 +12/-13 m/s. Moderate resolution spectroscopy of the host star has determined the following parameters: T_eff = 5598 +/- 63, log g = 4.44 +/- 0.17, and [Fe/H] = +0.40 +/- 0.09. Based upon these measurements, GSC 03546-01452 has a probable mass and radius of M_star = 1.11 +/- 0.11 M_Sun and R_star = 1.06 +/- 0.23 R_Sun with an age consistent with less than ~6 Gyr at a distance of 219 +/- 21 pc from the Sun. Although MARVELS-6b is not observed to transit, we cannot definitively rule out a transiting configuration based on our observations. There is a visual companion detected with Lucky Imaging at 7.7 arcsec from the host star, but our analysis shows that it is not bound to this system. The minimum mass of MARVELS-6b exists at the minimum of the mass functions for both stars and planets, making this a rare object even compared to other BDs.Comment: 15 pages, 15 figures, 5 tables. Accepted for publication in The Astronomical Journa

Very Low-Mass Stellar and Substellar Companions to Solar-Like Stars from MARVELS I: A Low Mass Ratio Stellar Companion to TYC 4110-01037-1 in a 79-day Orbit

TYC 4110-01037-1 has a low-mass stellar companion, whose small mass ratio and short orbital period are atypical amongst solar-like (Teff ~< 6000 K) binary systems. Our analysis of TYC 4110-01037-1 reveals it to be a moderately aged (~<5 Gyr) solar-like star having a mass of 1.07 +/- 0.08 MSun and radius of 0.99 +/- 0.18 RSun. We analyze 32 radial velocity measurements from the SDSS-III MARVELS survey as well as 6 supporting radial velocity measurements from the SARG spectrograph on the 3.6m TNG telescope obtained over a period of ~2 years. The best Keplerian orbital fit parameters were found to have a period of 78.994 +/- 0.012 days, an eccentricity of 0.1095 +/- 0.0023, and a semi-amplitude of 4199 +/- 11 m/s. We determine the minimum companion mass (if sin i = 1) to be 97.7 +/- 5.8 MJup. The system's companion to host star mass ratio, >0.087 +/- 0.003, places it at the lowest end of observed values for short period stellar companions to solar-like (Teff ~< 6000 K) stars. One possible way to create such a system would be if a triple-component stellar multiple broke up into a short period, low q binary during the cluster dispersal phase of its lifetime. A candidate tertiary body has been identified in the system via single-epoch, high contrast imagery. If this object is confirmed to be co-moving, we estimate it would be a dM4 star. We present these results in the context of our larger-scale effort to constrain the statistics of low mass stellar and brown dwarf companions to FGK-type stars via the MARVELS survey.Comment: 22 pages; accepted in A

Acute Respiratory Distress Syndrome Induced by a Swine 2009 H1N1 Variant in Mice

Background: Acute respiratory distress syndrome (ARDS) induced by pandemic 2009 H1N1 influenza virus has been widely reported and was considered the main cause of death in critically ill patients with 2009 H1N1 infection. However, no animal model has been developed for ARDS caused by infection with 2009 H1N1 virus. Here, we present a mouse model of ARDS induced by 2009 H1N1 virus. Methodology Principal Findings: Mice were inoculated with A/swine/Shandong/731/2009 (SD/09), which was a 2009 H1N1 influenza variant with a G222D mutation in the hemagglutinin. Clinical symptoms were recorded every day. Lung injury was assessed by lung water content and histopathological observation. Arterial blood gas, leukocyte count in the bronchial alveolar lavage fluid and blood, virus titers, and cytokine levels in the lung were measured at various times post-inoculation. Mice infected with SD/09 virus showed typical ARDS symptoms characterized by 60 % lethality on days 8–10 postinoculation, highly edematous lungs, inflammatory cellular infiltration, alveolar and interstitial edema, lung hemorrhage, progressive and severe hypoxemia, and elevated levels of proinflammatory cytokines and chemokines. Conclusions/Significance: These results suggested that we successfully established an ARDS mouse model induced by a virulent 2009 H1N1 variant without previous adaptation, which may be of benefit for evaluating the pathogenesis or therapy of human ARDS caused by 2009 H1N1 virus